Systems and methods of microfluidic membraneless exchange using filtration of extraction outlet streams

ABSTRACT

A device, system and method for exchanging components between first and second fluids by direct contact in a microfluidic channel. The fluids flow as thin layers in the channel. One of the fluids is passed through a filter upon exiting the channel and is recycled through a secondary processor which changes the fluid&#39;s properties. The recycled fluid is reused for further exchange. The filter excludes blood cells from the recycled fluid and prevents or limits clogging of the filter. The secondary processor removes metabolic waste and water by diafiltration.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.12/759,157, filed Apr. 13, 2010, currently pending, which is adivisional of U.S. application Ser. No. 11/814,117, filed Jul. 17, 2007,issued as U.S. Pat. No. 7,727,399 on Jun. 1, 2010, which is a U.S.national stage application of International Application No.PCT/US2007/069414, filed May 22, 2007, now expired, which claims thebenefit of U.S. Provisional Application Ser. No. 60/802,471, filed May22, 2006, all of which are hereby incorporated by reference herein intheir entireties.

FIELD OF THE INVENTION

The invention generally relates to component exchange between fluids.More specifically, the invention relates to selective separation of thecomponents of a sample fluid (e.g., blood fluid) by microfluidicmembraneless exchange.

BACKGROUND

Extracorporeal processing of blood is known to have varied uses. Suchprocessing can be used, for example, to provide treatment of a disease.To treat end stage renal disease, for example, hemodialysis is the mostcommonly employed form of extracorporeal processing for this purpose.Extraction of blood components can be used to remove other componentsfor treatment, such as free viral particles and, in the treatment ofcongestive heart failure, to remove water and a non-selective cohort ofelectrolytes. Additional uses for extracorporeal processing includeextracting blood components useful in treating disease conditions or inresearch and/or diagnosis. Apheresis of plasma (i.e., plasmapheresis)and thrombocytes, or platelets, is the procedure most commonly employedfor this purpose. Although the present specification describes primarilyblood processing and issues related thereto, many of the methodsdescribed may be used for processing other fluids as well.

Many different extracorporeal blood processing techniques have beendeveloped which seek to separate components from the blood. Thecomponent that is to be separated varies depending on the purpose of theprocess. It will be understood that as used herein, blood, or bloodfluid, refers to a fluid having blood components. It is desirable toextract components, such as metabolic products or poisons from the bloodfluid. These metabolic products can be small molecules or toxins oflarger molecular weight, generally termed “middle molecules.”

The most common process utilizes an artificial membrane of substantialarea, across which selected blood components are induced to flow. Thisflow is generally induced by a transmembrane difference in eitherconcentration or pressure, or a combination of the two. Another form ofblood processing calls for the separation of components from blood bypassing the blood over sorbent particles. In yet other forms of bloodprocessing, blood is directly contacted with an immiscible liquid (e.g.,a fluorocarbon liquid), with the desired result being the removal ofdissolved carbon dioxide and the provision of oxygen. The usefulness ofblood processing techniques employing immiscible liquids is limited,however, because these immiscible liquids generally have limitedcapacity to accept the blood components that are desirable to extract.

One common example of a therapeutic use for blood processing is for themitigation of the species and volume imbalances accompanying end-stagerenal disease. The population of patients treated in this manner (e.g.,through hemodialysis) exceeds 300,000 in the United States and continuesto grow, with the cost of basic therapy exceeding $8 billion per yearexcluding complications. The overwhelming majority of these patients(about 90%), moreover, are treated in dialysis centers, generally inthrice-weekly sessions. While procedures have been, and continue to be,refined, the basic components and methods of the most common treatment,hemodialysis, were largely established in the 1970's. A typicalhemodialysis device consists of a bundle of several thousand permeablehollow fibers, each of which is about 25 cm long and about 200 μm ininternal diameter. The fibers are perfused externally by dialyzingsolution. The device is operated principally in a diffusive mode, but atransmembrane pressure is also applied to induce a convective outflow ofwater. Upwards of 120 liters per week of patient blood are dialyzedagainst upwards of 200 liters per week of dialyzing solution, often inthree weekly treatments that total seven to nine hours per week. Thesenumbers vary somewhat, and competing technologies exist, but the basicapproach just described predominates.

Despite the benefits of therapies (e.g., hemodialysis) using the variousforms of blood processing described above, the prolongation of lifeachieved is complicated by the progression and complexity of thediseases that the therapies are used to treat, and by several problemsthat are innate to the therapies themselves. Few patients on dialysisare ever completely rehabilitated. Problems arise with blood processingas a result of the contact of blood with the surfaces of artificialmembranes, sorbents, or immiscible fluids, as described above. Suchcontact often induces biochemical reactions in the blood beingprocessed, including the reactions that are responsible for clotting,activation of the complement systems, and irreversible aggregation ofblood proteins and cells.

Another problem associated with known blood processing techniques isthat the contact of blood with artificial membranes or sorbents cancause the blood-medium interface to become fouled. It is generally knownthat blood purification procedures (e.g., those related to end-stagerenal disease) are optimally conducted in such a manner as to maintain ahealthy equilibrium state. In practice it has been recognized thattreatment should be performed at a limited rate and in as nearly acontinuous fashion as possible to avoid the consequences of rapidchanges in the composition of body fluids, such as exhaustion andthirst. However, fouling caused by the contact of blood with theartificial materials limits the time that devices with such materialscan be usefully employed.

Fouling due to artificial surface-induced blood coagulation can bemitigated with anticoagulants but at unacceptable risk to the ambulatorypatient. As a result, portable blood processing devices becomeimpractical, and patients are generally forced to undergo the type ofepisodic dialysis schedule described above. A solution to these problemsis needed if sustained, ambulatory treatment is to replace episodicdialysis.

The reasons for episodic treatment are many. For example, thebio-incompatibility, mentioned above, the lack of a portable device, thecurrent need for blood circulation outside the patient, and the feelingof many patients that they are unable to manage the treatment processthemselves (particularly because of the need to puncture the patient'sblood vessels). Thus, while daily dialysis (e.g., 1.5-2.0 hours, sixdays per week) or nocturnal dialysis (e.g., 8-10 hours, 6-7 nights perweek) extends treatment times, many patients are unwilling or unable touse one of these forms of treatment.

Devices that provide for direct contact between blood and dialysis fluidfor the purpose of treatment and analyte extraction have been proposed.For example, US Patent Pub. No. 2004/0009096 to Wellman describesdevices in which blood and dialysate are in direct contact with eachother. Another example, U.S. Pat. No. 5,948,684 to Weigl, relates to theapplication of analyte separation.

SUMMARY OF THE INVENTION

In general, the present invention features filters to introduce andremove extraction fluids from a microfluidic membraneless exchangedevice. Embodiments of the invention can be used for selectivelyremoving undesirable materials from a sample fluid (e.g., blood fluid)by contact with a miscible fluid (e.g., extraction fluid or secondaryfluid). In one embodiment, the pores of the filters are arranged in thedevice so as to substantially avoid contact with the blood fluid.

Sheathing a core of blood with the miscible fluid, or assuring that themiscible fluid lies between at least a substantial portion of the bloodand the enclosing boundaries of the flow path, prevents, or at leastlimits, contact of the blood with these boundaries. Likewise, in someembodiments, the extraction fluid substantially inhibits contact betweenthe blood and the filters. In turn, this configuration of the two fluidsprevents, or at least reduces, the undesirable activation of factors inthe blood, thereby reducing bio-incompatibilities that have beenproblematic in prior techniques of blood processing.

A microfluidic device, as considered in this application, has channelswhose height is less than about 0.6 mm, where “height” is the dimensionperpendicular to the direction of flow and also perpendicular to theinterface across which transport occurs. As described in greater detailbelow, advantages are realized by using channels whose height is about75 μm. However, channel heights can be a great as 0.6 mm. Smallerchannel heights decrease the time needed to diffuse components from thesample fluid into the secondary fluid, resulting in higher performanceand reduced device size as compared to larger channel heights. Thesecondary fluid, moreover, is generally miscible with blood anddiffusive and convective transport of all components is expected.However, the diffusive and convective transport is accomplished withoutturbulent mixing of the sample fluid and the secondary fluid. Thesecondary fluid is withdrawn from the channels of the microfluidicdevice through thin barriers with pores, e.g., filters, having criticaldimensions ranging from about one micrometer to about 50 nanometers.

As described above, the height of the extraction channel can be about 75μm. Thus, the height of the two layers of extraction fluid and singlelayer of sample fluid (e.g. a blood fluid) are necessarily less than 75μm. In one embodiment, the extraction channel is about 75 μm high andeach fluid layer is about 25 μm high. The extraction fluids areintroduced into the extraction channel in such a way as to maintain theextraction fluid along the walls of the extraction channel. Thecombination of extremely thin layers of fluid and the absence of amembrane along the diffusive interface result in high transport speedsas compared to those speeds obtained using membrane-based devices.Higher transport speeds allow for the total area of fluid contact to berelatively small as compared to membrane-based devices. Similarly,surfaces in contact with the blood fluid adjacent to the extractionchannel, such as the blood fluid inlet channel surface before reachingthe extraction region, can also be relatively small. Thus, the totalamount of contact between the blood fluid and artificial surfaces isreduced. This aspect of the invention provides increasedbiocompatibility.

Withdrawing the miscible fluid (i.e., extraction fluid) from themicrofluidic extraction channel through a filter prevents the build-upof certain components in the extraction fluid. For example, blood cellsmay migrate from the blood into the extraction fluid during the timewhen the fluids are in contact in the microfluidic extraction channel.In some operating scenarios, this migration is undesirable. As describedin greater detail below, the characteristics of the fluid flows can becontrolled to cause blood cells to concentrate in the middle of theblood fluid stream. This reduces the amount of blood cells that diffuseinto the extraction fluid, but some cell migration may still occur.Appropriate pores in the filters inhibit departure of this small numberof blood cells from the extraction channel with the extraction fluid.Moreover, the high shear rates characteristic of microfluidic flowsprovide a shear force at the surface of the filter sufficient to “sweep”this surface. Because the number of blood cells in the extraction fluidare kept relatively low, this sweeping action facilitates keeping thesurface of the filter clear of blood cells, thus aiding in thepreventing of clogging.

Similarly, other blood components can be inhibited from exiting theextraction channel with the extraction fluid. For example, the proteinfibrinogen is capable of clotting, and it can be desirable in someembodiments to prevent fibrinogen from exiting the extraction channelwith the extraction fluid. Thus, the pores of the filters can be sizedto keep fibrinogen in the extraction channel, for example, by usingfilters with a pore size of about 50 nm. In addition, fluid flowcharacteristics, fluid interface velocity, and fluid contact time can becontrolled to complement the selection of pore size in preventing lossof certain blood components and in preventing fouling.

Various embodiments also eliminate or at least substantially reduce thefouling reactions that have been known to be a major deterrent to thecontinuous use of an extracorporeal extraction device. In particular, asthe primary transport surface in the membraneless exchange device (alsoreferred to herein as a membraneless separator or extraction channel) isintrinsically non-fouling because of the increased biocompatibility andbecause the interface is constantly renewed. Thus, a major deterrent tolong-term or continuous operation is removed, opening the possibility tothe design and construction of small, wearable devices or systems withthe recognized benefits of nearly continuous blood treatment. Such adevice or system could be very small and worn or carried by the patient(e.g., outside of a hospital or clinic setting), and could be suppliedwith external buffer reservoirs (in a back-pack, briefcase, or from areservoir located in the home, located at the place of work, etc.).Further, because fouling would be reduced, and sustained operation atlow blood flows over long times would be allowed, such anticoagulationas might be required could be administered as blood left the body andcould be adjusted to have an effect confined to the extracorporealcircuit. As understood by those skilled in the art, avoiding systemicanticoagulation outside of the clinic is highly desirable.

Some of the devices, systems and methods described herein are capable ofdiffusing various blood components having different sizes. In addition,the flow of blood and a miscible fluid with which it is in contact canbe controlled for the purpose of achieving the desired separation ofcellular components. For example, as explained below, various flowconditions can be used that cause blood cells to move away from theblood-liquid interface, thereby making it possible to “skim” blood inorder to remove substantial amounts of plasma, without cells. Thefilters aid in accomplishing this skimming effect by inhibiting theremoval of cells that may have migrated into the miscible fluid despitethe tendency of cells to move away from the blood-liquid interface atparticular flow conditions.

As also discussed below, membraneless contact of a thin layer of bloodwith a extraction fluid can be used to cause high rates of exchange perunit area of blood-extraction fluid contact for all solutes. Thediscrimination among free (unbound) solutes will generally be less thanthe square-root of the ratio of their diffusion coefficients. While highexchange rates of particular substances are desired, indiscriminatetransport is not. Therefore, a primary membraneless exchange device withfilters on the extraction fluid outlets as described herein is used inconjunction with at least one secondary processor (e.g., a membranedevice or other type of separator) in order to restrict the removal ofdesirable substances and effect the removal of undesirable substancesfrom blood. The efficiency of such a secondary processor is greatlyincreased by the use of the primary separator that is capable ofdelivering cell-depleted (or cell-free) fractions of blood to it.

Therefore, in an example membraneless exchange device, transport ofmolecular components of blood to the extraction fluid can beindiscriminate. The extraction fluid, carrying both those molecularcomponents that are, and are not, desirable to remove from blood, isprovided to the secondary processor. The secondary processor regulatesthe operation of the membraneless separator through the composition ofthe recycle stream that it returns (directly or indirectly) to theextraction fluid inlets of the membraneless separator. Moreover, amembrane-based secondary processor used in this manner is able toachieve much higher separation velocities because cells, which are shearsusceptible, are not present. Furthermore, concentration polarization(i.e., the accumulation of material rejected by the secondary processoron the upstream side of the separator) is limited to proteins and doesnot involve cells, and concentrations of proteins in the extractionfluid can be regulated by selection of filter pore size, fluid flowcharacteristics, and fluid contact time. Moreover, because cells wouldbe retained in the primary separator (i.e., the membraneless exchangedevice), they would see artificial material only on its conduitsurfaces, not on its liquid-liquid contact area, whencebio-incompatibilities should be much reduced. As such, it should beunderstood that the need for anticoagulation may be greatly reduced oreliminated.

Approaches to ameliorating the problems created by contact between theblood and an artificial membrane are described in U.S. patentapplication Ser. No. 10/801,366, entitled Systems and Methods ofBlood-Based Therapies Having a Microfluidic Membraneless ExchangeDevice, filed Mar. 15, 2004, and U.S. patent application Ser. No.11/127,905, having the same title, filed May 12, 2005, both hereinincorporated by reference as if fully set forth in their entiretyherein.

According to an embodiment, the invention is a method for exchangingcomponents between a first fluid and a second fluid. The method beginswith forming respective layers of first and second fluids such thatdiffusion-based exchange of components between the first and secondfluids occurs in the absence of mixing. For example, the fluids can flowinto a laminar flow channel. According to the method, at least a portionof the first fluid flows through pores sized to block first componentsfrom the second fluid while passing second components from the secondfluid. For example, the first component could be blood cells, if thesecond fluid were blood and the second components could include largeand small molecules such as albumin and electrolytes. In a moreparticular variation of this embodiment, the filtering includes passingthe first fluid through pores whose size is smaller than 800 nm. In thecase where the second fluid includes blood, the pore size is preferablysmaller than this size and even more preferably, substantially less, forexample, less than 600 nm.

Preferably the layers are formed by flowing the first and second fluidsthrough a channel, and the filtering includes providing a filter forminga portion of a wall of the channel. Preferably the filter defines asmooth continuous surface that is coplanar with the wall of the channel.By doing this, the filter can remain clear of materials which maycollect on the surface. This is particularly true where the channel hasa small dimension in a direction normal to the surface of the filter, asis preferred, because the high shear rates of fluid resulting from thenarrow space help to scour the surface of the filter. This feature isparticularly preferred in embodiment where blood is the second fluidbecause proteins in the blood and cells might get stuck in a filter thatdoes not have a relatively smooth surface. In addition, preferably, thepores define non-serpentine, non-branching channels.

In another preferred variation of the foregoing methods, there are twofirst layers with a second layer between them. In this way, the secondlayer may be sheathed by the first layer, if the channel within whichthey flow, has a suitable aspect ratio, which is preferred. Such asandwich of flowing sheets of fluid provides high contact area and canprovide a very low Reynolds number such that no mixing occurs, yet veryeffective diffusion between the layers is achieved. Preferably thechannel's cross-section aspect ratio is greater than ten and morepreferably, it is greater than 50. Preferably, the depth of the channel(the short dimension of the cross section) is between 75 and 500 micronsand even more preferably, it is about 120 microns.

In a preferred variation of the foregoing method embodiments, the firstfluid is generated by concentrating the second component in the filteredfirst component and recycling it back into the first layer or layers.This can be done by taking the filtrate from the filtering of the firstfluid and passing it through fluid processor that removes fluid from thefirst fluid while leaving the second component behind. For example thiscan be done by ultrafiltration and recovering the filtrand and recyclingthe same. This can also be done, for example, by adding more of thesecond component to the recycled stream. For example, the secondcomponent could be serum albumin, where the second fluid it blood.

According to an embodiment, the invention is a method for clearing firstcomponents from a first fluid, comprising: flowing a layer of the firstfluid surrounded by at least one co-flowing layer of solvent to isolatethe layer from the wall of a conveying channel while permittingdiffusion of the first component from the first fluid into the solutewithout mixing and removing the first component from the solvent andreplenishing the co-flowing layer of solvent with a result of theremoving. In an embodiment, the first fluid is blood. In the latterembodiment, the solvent is preferably an aqueous solution. The removingpreferably includes filtering solvent by passing it through a filter andpassing the resulting filtrate across another filter and recovering thefiltrand therefrom, the fitrand being the result of the removing. Theremoving may include filtering solvent by passing it through a filterand passing the resulting filtrate across another filter and recoveringthe filtrand therefrom, the fitrand being the result of the removing. Inan embodiment where the first fluid is blood, in a preferred embodiment,the removing includes filtering the solvent to block blood cells. Forexample, where the first fluid is blood, the removing may includedialyzing the solvent at a location remote from blood cells andreturning the dialyzed solvent to the co-flowing layer to permit thediffusion of blood proteins back into the blood.

According to an embodiment, the invention is a method of processingblood. The method includes concurrently flowing blood and an aqueoussolvent through a channel with a wall portion having a regular patternof pores in a wall thereof, the pores having a maximum size less than 1micron. The method further includes circulating the solvent through aflow circuit that includes the pores and returns the solvent back to thechannel at a point upstream of the pores. The flow circuit preferablyincludes a processor that removes water from the solvent and morepreferably, also removes uremic toxins from the solvent. Preferably, thepores have a maximum size of less than 600 nm.

Preferably, in the latter embodiment, the flowing creates a flow thatkeeps blood cells from contacting substantially all of the wall surface.Preferably, the pores have a maximum size of about 100 nm or less. Theconcurrently flowing preferably includes flowing blood and aqueoussolvent at approximately equal volume rates in the channel.

According to another embodiment the invention is a fluid processingdevice with a channel having a ratio of width to depth of more than 10.The depth is no more than 300 microns and both the width and the depthare perpendicular to a direction of flow. The channel has an input endand an output end separated by a length, which is parallel to thedirection of flow. Two inlet extraction fluid ports and one inlet samplefluid port, located between the two inlet extraction fluid ports, arepositioned proximal to the input end and two outlet extraction fluidports and one outlet sample fluid port between the two outlet extractionfluid ports are positioned proximal to the output end. The outletextraction fluid ports having first filters. At least one of the outletextraction fluid ports is coupled by a flow channel, other than thechannel, to at least one of the inlet extraction fluid ports.

Preferably, the channel has a wall surface with dimensions are equal tothe width and the length, the first filters forming a portion of thewall. Preferably, the first filters have a pore size no greater than1000 nm, more preferably, no greater than 800 nm and even morepreferably, no greater than 300 nm. Preferably, the channel has a depthof no more than 120 microns. In a preferred variation, theaforementioned ratio of width to depth is more than 50. In a variation,the embodiment has at least one pump configured to pump at least 1 literof blood and at least one liter of solvent through the channel during atreatment cycle lasting no more than one day.

In a particularly preferred variation of the foregoing embodiments, theinlet and outlet sample ports are connected to channels with connectorsconnectable to arterial and venous lines of a patient access.

According to another embodiment, the invention is a device forexchanging components between a first fluid and a second fluid, wherethe second fluid contains first and second components. The deviceincludes a channel that receives a first fluid and a second fluid toform at least one first layer and at least one second layer of the firstand second fluids, respectively, such that they are in direct contactwith each other and do not mix. The at least one first layer and atleast one second layer flow in a same flow direction. The channel hasoutlets with at least one filter that receive only the first fluid, theat least one filter having pores sized to block the first componentsfrom the second fluid while passing the second components from thesecond fluid. Preferably, the at least one filter has pores whose sizeis smaller than 800 nm. The channel has walls and the at least onefilter preferably defines a portion of the channel wall. In a preferredvariation, the at least one first layer is two layers and the at leastone second layer is one layer, the second layer being positioned betweenthe two first layers. Preferably the pores define direct channels whichare non-serpentine and non-branching. In a preferred embodiment, thefirst components are erythrocytes.

The first fluid preferably includes a fluid obtained by increasing theconcentration of the second component in a filtrate obtained frompassing the first fluid through the at least one filter. Preferably, thesecond component includes serum albumin. Preferably, the channel haswalls and the at least one first layer is two first layers and theforming includes forming the two first layers with a single second layerbetween them such that the first fluid prevents the second fluid fromdirectly contacting the walls. Preferably, the channel may have across-section cutting across the flow direction whose aspect ratio isgreater than ten. Preferably, the channel has a depth across the flowdirection between 75 and 300 microns. Most preferably, the depth isabout 120 microns.

According to another embodiment, the invention is a device forexchanging components between a first fluid and a second fluid. Thedevice has first and second channels, each having respective inlets andoutlets to permit at least two fluids flowing into the inlets to flowco-currently therethrough, in direct contact with each other, and toflow out of the outlets. The device further contains a fluid processor,with an inlet and an outlet, which changes a property of fluids receivedat the inlet and conveys a changed fluid to the outlet. A first of thefirst channel outlets is connected to a first of the second channelinlets. A second of the first channel outlets is connected to the fluidprocessor inlet. A second of the second channel inlets is connected tothe fluid processor outlet.

Preferably, the fluid processor includes a membrane, for example, adialyzer. A fluid conveyance may be provided to cause fluids to flowthrough the first and second channels in laminar fashion such thattransport between the fluids in the channels is primarily by diffusion.Preferably, the second of the first channel outlets contains a filter.Preferably the filter has pores whose sizes are a maximum of 600 nm.

According to an embodiment, the invention is a method of separatingblood cells from plasma. The method includes drawing most of the bloodcells, in a layer including blood cells and plasma, away from a vesselsurface having a filtered outlet and removing the plasma through thefiltered outlet to block blood cells entering the outlet. In anembodiment, the layer is a flowing layer and in a variation of theembodiment, the drawing includes creating a shear gradient in theflowing layer that is higher near the wall than remote from the surface.Preferably, the layer includes an aqueous solvent. The filtered outletpreferably has a filter with a surface that is coplanar with the vesselsurface. In this case, where the layer is a flowing layer having a shearnear the surface, the shear scours the surface of the filter.

Further features of the invention, its nature and various advantages,will be more apparent upon consideration of the following detaileddescription, taken in conjunction with the accompanying drawings, inwhich like reference characters refer to like parts throughout.

BRIEF DESCRIPTION OF THE DRAWINGS

The accompanying drawings, which are incorporated herein and constitutepart of this specification, illustrate presently preferred embodimentsof the invention, and, together with the general description given aboveand the detailed description given below, serve to explain features ofthe invention.

FIG. 1A shows the velocity profile of a core stream of blood sheathed onboth of its sides by an extraction fluid calculated for blood with aviscosity assumed twice that of the extraction fluid and with acenterline velocity of 5 cm/sec.

FIG. 1B is a figurative illustration of an extraction channel.

FIG. 2 shows a plot using Loschmidt's formula of 1870, describingdiffusive exchange between two fluid layers, each fluid layer has thesame thickness, B.

FIG. 3 shows a simplified view of a membraneless separator with filtersin the extraction fluid inlets and outlets.

FIG. 4 shows a partial close-up perspective view of an area around anopening of an outlet channel, including a filter, of the membranelessseparator of FIG. 3.

FIG. 5 shows an outline of another possible embodiment of a membranelessseparator.

FIG. 6 shows an example of a filter.

FIG. 7 shows a close-up side view of a filter illustrating a fluidsweeping action across the surface of the filter.

FIG. 8 shows a membraneless separator with filters used for the purposeof plasmapheresis.

FIG. 9 shows a simplified block diagram of a membraneless separatorsystem including a membraneless separator with filters and a secondaryprocessor.

FIG. 10 shows a more detailed view of a system including primary andsecondary processors.

FIG. 11 shows the configuration of a system subdivided into two units,arranged to achieve a pseudo-countercurrent flow of sample andextraction fluids.

DETAILED DESCRIPTION OF THE INVENTION

An exchange device extracts selected components from a sample fluid. Theexchange device passes an extraction fluid and a sample fluid in laminarflow through a common extraction channel such that the extraction andsample fluids come in direct contact, but remain in defined layersthroughout the common extraction channel. Preferably, the extractionchannel has dimensions that assure laminar flow conditions aremaintained even under conditions of normal use and that permit a largeinterface area between the sample and extraction fluids in a compactdesign. As such, the channel and its related components have thedimensions which may be characterized by the term, microfluidic.

Referring to FIGS. 1A and 1B, in a preferred configuration, the samplefluid 104 is blood, which flows in a layer that is sandwiched betweentwo extraction fluid layers 102 all of which flow together through anextraction channel 105. Relative to the oriented drawing page in FIG.1A, the extraction channel 105 has a width going into the page, a lengthin the horizontal direction, and a depth in the vertical direction.Generally, as used herein, the term “width” refers to a dimensionperpendicular to the direction of flow and parallel to the interfacebetween the two liquids, “depth” refers to a dimension perpendicular tothe direction of flow and to the interface between the two fluids, and“length” refers to the dimension parallel to the flow direction.Superimposed on the extraction channel 105 is a graph, with axes, toshow the velocity profile of the sample 104 and extraction 102 fluidlayers.

The flow in the extraction channel 105 creates two liquid-liquidboundaries 110 between the sample fluid 104 and the two extraction fluid102 layers. The extraction channel 105 can be configured so that itsubstantially isolates the sample fluid 104 from the artificial walls107 of the extraction channel 105 while the sample fluid is in theextraction channel 105. For example, in a preferred configuration, theextraction channel 105 is many times wider and longer than it is deep.As a result, the sample fluid 104 contacts the extraction fluid 102 overa large area (length×width), but contacts the artificial walls 107 ofthe channel over a much smaller area (length×depth=2B of sample layer)at the lateral edges. This helps to provide a large interface betweenthe sample 104 and extraction 102 fluids and effectively isolates thesample fluid 104 from the walls of the extraction channel.

A preferred extraction channel 105 has inlets 125 which convey fluidinto the extraction channel 105 adjacent the walls 107. The extractionchannel includes respective outlets 123, displaced in a length directionfrom the inlets 125, which draw extraction fluid 102 from the extractionchannel 105. The sample fluid 104 flows into and out of an aligned inlet127 and outlet 129, respectively. The details of embodiments of theinlets and outlets 123, 125, 127, and 129 are described with respect toembodiments below. In a preferred embodiment of an extraction channel105, usable for renal replacement therapy, the sample fluid 104 is bloodand the extraction fluid 102 is an aqueous solution such as dialysate.As explained in more detail below, the blood cells tend to remain in thesample fluid 104 layer because they diffuse more slowly than smallparticles, such as proteins and ionic species. Cells are also subject totendency to migrate toward the low shear regions of the flow, which isat the center of the extraction channel 105. (The tendency of cells tomigrate to low shear regions is described in Goldsmith, H. L. and Spain,S., Margination of leukocytes in blood flow through small tubes,Microvasc. Res. 1984 March; 27(2):204-22.) In a preferred embodiment,cells, or other large particles, may also be blocked from exiting theextraction fluid outlets 123 by filters (not shown in FIGS. 1A and 1B),which are described in more detail below.

The velocity profile 112/114 is calculated for a situation where theproperties of the sample fluid 104 are the same as for the extractionfluid 102. The velocity profile 112/114 is consistent with the classicsingle fluid profile assumed by a laminar flow in a two-dimensionalchannel. The velocity profile 112/116, however, exhibits blunting, whichresults when the sample fluid 104 has a higher viscosity than theextraction fluid 102. This is the case when the sample fluid 104 isblood and the extraction fluid 102 is dialysate. Note that FIG. 1A showsa calculated condition for the situation where there is a substantiallyclear boundary 110 between the sample 104 and extraction 102 fluids. Inan actual device, the properties of the fluids may blend as theboundaries 110 become less distinct due to diffusion of fluid componentsthereacross.

Transport of molecules within the extraction channel 105 is preferablynon-turbulent with no mixing. By providing a flow configuration withselected flow rates and a channel size, mixing can be reliablyprevented. If configured to function as a dialyzer, the device enablestreatments with brief contact time between blood and artificialmaterials, low extracorporeal blood volume, and very compact size in amicrofluidic device. Note that as used herein, the term “extracorporeal”is not necessarily limited to the removal of blood from the patient bodyenvelope and microfluidic extraction channels that are implanted in thebodies of patients are not intended to be excluded from the scope of theinvention.

In a renal replacement therapy embodiment, where the sample fluid 104may be whole blood, it is contemplated that only non-cellular componentsof the blood are extracted by the extraction channel 105. The flow ofextraction fluid 102 in the extraction channel 105 can be controlledindependently of the flow of blood in the extraction channel 105 usingan appropriate combination one or more injection pumps 130 and 132, andwithdrawal pumps 134, 136. For example a first injection pump 132 mayinject extraction fluid 102 into the extraction channel 105 and a firstwithdrawal pump 134 may withdraw extraction fluid 102 out of theextraction channel 105. Similarly respective injection and withdrawalpumps 130 and 136 may inject and withdraw sample fluid 104 into and fromthe extraction channel 105, respectively. By controlling the relativerates of the pumps 130-136, the change in total volume of the bloodexiting the extraction channel 105 can be varied. In a blood treatmentembodiment, the control of the inflow and outflow rates is used toregulate a patient's fluid volume, which is a conventional requirementof renal replacement therapy. In this embodiment, the extraction channeldepth (6B as shown in FIG. 1) is preferably in the range of 70 to 300 μmand more preferably, approximately 120 μm. Preferably, the extractionchannel 105 has a width-to-depth ratio of at least ten. Preferably,width-to-depth ratio is greater than 50 and more preferably greater than500. Note that although the figurative depiction in FIG. 1B shows fourpumps, other embodiments could employ a smaller or greater number ofpumps.

Referring to FIG. 1A, the velocity profile 112/114 of the core samplefluid 104 layer, sheathed on both of its sides by the extraction fluid102 layers, is calculated for blood with a viscosity, μ_(B), assumed tobe twice that of the extraction fluid, μ_(S) and with a centerlinevelocity of 5 cm/sec. At this centerline velocity, a flow path length of10 cm would result in a contact time of slightly longer than 2 sec. Thediffusion of constituent particles (of all sized, from small ions tocells) resulting from steady contact of two moving liquids for anexposure time determined by the length of their contact area divided bytheir interfacial velocity (τ=L/ν) is analogous to the instant exposureof one volume of stagnant fluid to another for a specified time. Thus,what happens to the flowing fluids along their shared flow path iscomparable to what happens to two stagnant fluids exposed to each otherfor a finite period of time. The stagnant fluid problem was solved byLoschmidt in 1870.

$E = {\frac{1}{2} - {\frac{4}{\pi^{2}}{\sum\limits_{0}^{\infty}{\frac{1}{\left( {{2n} + 1} \right)^{2}}{\exp\left\lbrack {{- \left( {{2n} + 1} \right)^{2}}\left( \frac{\pi}{2B} \right)^{2}{Dt}} \right\rbrack}}}}}$for which the zeroth order term,

$E = {\frac{1}{2} - {\frac{4}{\pi^{2}}{\exp\left\lbrack {{- \left( \frac{\pi}{2B} \right)^{2}}{Dt}} \right\rbrack}}}$suffices when

${\left( \frac{\pi}{2B} \right)^{2}{Dt}} > 0.7$

This formula greatly simplifies the estimation of how much mass can betransferred between fluids in a membraneless system. In particular, thisformula provides an approximation of the extraction E of a componentwith a diffusion coefficient D when two liquids flow side-by-side andremain in contact for an interval of time, t.

FIG. 2 shows a plot of extraction versus

$\left( \frac{\pi}{2B} \right)^{2}{Dt}$using a version of Loschmidt's formula, where each fluid layer has thesame thickness B (i.e., B is the half-thickness of the sheathed layer ofsample fluid). The situation shown in the plot of FIG. 2 can beinterpreted as a blood layer, of thickness B, contacting a layer ofextraction fluid (i.e., extraction fluid). The sheathing layer ispresumed to be at zero concentration and E is the fraction of materialin the blood layer that is extracted in a time t, where D is thediffusion coefficient of the extracted substance. If a layer ofthickness twice B is bounded on both sides by fluid layers of thicknessB, the formula still applies, as written. As indicated by this formula,E cannot exceed 0.5 since, in co-current flow, the highest extractioncorresponds to equilibrium of the two fluids.

If 90% of the maximum possible extraction (which is E=0.45) is desired,the ratio Dt/B must be approximately 0.86. Any combination of diffusioncoefficient, blood layer thickness, and exposure time that produces thisvalue, will produce the same extraction. Moreover, it can be shown thatthe necessary area (2LW) to achieve this extraction equals 0.86 BQ/D,where Q is the blood (and extraction fluid) flow rate. Thus, for urea(D=10 cm at a blood flow rate of 0.300 cm³/s) the required area is2.58·B·10⁴ cm². If B is taken to be 100 μm, the required area is 258cm². This flow corresponds to what might be needed in a wearableartificial kidney. If, instead, a conventional flow rate of 5 cm³/s wereused, the required area would be 4300 cm². If thinner films are used,even less area is required to reach a specified extraction.

In terms of extraction, combinations of length L and width W may bevaried to produce the required area and a specified extraction rate. (Ifone assumes D for albumin to be 5·10⁻⁷ cm²/s, its extraction would be0.116, 26% of that for urea.) An increase in channel depth raises therequisite contact time and may tend to reduce the stability of thesheathed flow. When total blood layer thickness is 25, 50, or 100 μm,and the blood flow is 20 ml/min (as it might be with a wearableartificial kidney), the interfacial area needed to cause a substance,such as urea (5·10⁻⁷ cm²/s) to reach 90% of equilibrium is,respectively, 18, 36, and 71 cm². Thus, as these examples show, incertain embodiments, it is desirable to have a total blood layerthickness of about 25 μm. Although desirable, this thickness is notessential and other considerations may make it desirable to provide fora different blood layer thickness in a blood treatment embodiment. Also,the above calculations apply to a dialysis-type blood treatment. Asnoted, however, the invention can be applied to other types of exchangeprocesses and fluids.

It should be noted that use of the Loschmidt formula with flowingsystems introduces an incongruity that prevents precise estimation ofmass transfer rates and clearances, given that it presumes that bothfluids are moving at uniform velocity. In particular, it provides anexcellent approximation for the sheathed fluid (blood), but ignores thenearly linear decay in velocity with distance from the interface in theextraction fluid. Nevertheless, the Loschmidt formula is adequate fordesign purposes when the sheathing layer has a total thickness (2B) thatis twice that of its half of the blood layer (B) (as shown in FIG. 1A),and thus a rate of flow nearly equal to its half of the central stream.

A shear-induced self-diffusion coefficient of cells D_(particle) can beestimated by using an expression provided by Leighton and Acrivos (1987)for concentrated suspensions: D_(particle)∝φ²a²{dot over (γ)}², where φis the particle volume fraction, a is the particle radius, and {dot over(γ)} is the shear rate. Then, the characteristic displacement of a cellcan be expressed as Δy∝√{square root over (D_(particle)t)}. Choosingrepresentative values for the layered flow system such that the cellvolume fraction φ≅0.45/2=0.225, the average radius a of the red bloodcell≅2.5 μm, and the average shear rate {dot over (γ)} over the bloodlayer≅3 to 28 s⁻¹ (based on an average velocity range of 0.5 to 5 cm/s),we calculate that D_(particle)˜10⁻⁸ cm²/s, which is approximately threeorders of magnitude smaller than the typical diffusion coefficient ofsmall solutes. Based on this value of the shear-induced diffusioncoefficient (and assuming 10 sec of contact between layers), it isestimated that blood cells are displaced by a characteristic distanceΔy≅3 to 9 μm from the central layer, depending on the choice of bloodvelocity and the concomitant shear rate. This low distance of cellmigration away from the central layer facilitates the removal ofcell-free portions of the blood.

For a number of reasons, a membraneless extraction channel 105 thatrelies solely upon the differences in the diffusion rates of smallversus large particles (that is, small molecules versus macromoleculesor even cells) may not be sufficiently discriminating to provide a basisfor blood treatment. For example, a practical system for renalreplacement therapy preferably prevents the sample fluid 104 retrievedfrom outlet 129 from being depleted of a significant fraction of themacromolecules, such as serum albumen, entering at inlet 127. Inaddition, the system should also prevent the loss of blood cells. In theembodiments discussed below, additional features are combined with theextraction channel discussed above, to provide benefits of a directcontact exchange but with the high degree of discrimination normallyassociated with membranes.

FIG. 3 shows a simplified side view of an extraction channel 300. Theextraction channel can be created using various techniques, for example,using wEDM (wirecut electric discharge machining) methods. Theillustrated embodiment includes an extraction channel 302 which receivefluids from three separate inlet channels 304, 306 and 308. Fluid fromthe extraction channel 302 leaves the channel through three respectiveoutlet channels 310, 312 and 314. Inlet channel 304 has an opening 316connecting inlet channel 304 to extraction channel 302. Likewise, inletchannel 308 has an opening 318 connecting inlet channel 308 toextraction channel 302. Outlet channels 310 and 314 have correspondingopenings 320 and 322 to extraction channel 302. Extraction fluid flowsalong the top surface of the extraction channel in a laminar fashionfrom inlet channel 304 to outlet channel 310 and in a similar fashionalong the bottom surface from inlet channel 308 to the outlet channel314.

Filters are preferably placed in all or some of openings 316, 318, 320,and 322 by which extraction fluid enters and leaves the extractionchannel 302. For example, in the embodiment of FIG. 3, filters 324 and326 are located in openings 316 and 318 of inlet channels 304 and 308,respectively and filters 328 and 330 are located in openings 320 and 322of outlet channels 310 and 314, respectively. The length of extractionchannel 302, between filter 326 and filter 330, is preferably about 1-2cm. The length of the filters can be about 3-4 mm (as shown by L in FIG.4). An aggregate extraction channel width, for example 30 cm, can beobtained by running multiple extraction channels in parallel. FIG. 4shows a partial close up perspective view of the area around opening 322of outlet channel 314 of extraction channel 300 of FIG. 3. A filter 330is placed in opening 322 connecting outlet channel 314 with extractionchannel 302. In one example embodiment, filter 330 has a cross-sectionin the shape of an inverted “T”, as shown in the figure. Opening 322 ofoutlet channel 314 has two opposed grooves 404 formed in side walls 406of opening 322. Grooves 404 receive two opposed tabs 408 of filter 330.This design enables filter 330 to be installed by sliding the filter 330into place. Likewise, the filter 330 can be removed from outlet channelopening 322 by sliding the filter 330 out of the outlet channel opening322. Thus, this example design allows for easy replacement of filter330.

Filter 330 can be of such size and shape as to eliminate gaps betweenopening 322 and filter 330, thereby forcing the extraction fluid to flowthrough the pores in the surface. Alternatively, the filters can befitted in recesses with upstream and downstream steps to support themsuch that a flat surface is of the filter faces the extraction channel302. Various techniques can be used to gain access to opening area 322in order to install or remove filter 330. For example, the side ofextraction channel 300 can be sealed with a removable plate. Thus, byremoving the plate, one can gain access to openings 316, 318, 320, and322. Various mechanical mounting configurations for the filters arepossible including the integral formation of the filters in thematerials used to create the channels 304, 306, 308, 302, 310, 312, and314.

Note that in a blood treatment device, filters 328 and 330 arepreferably provided to ensure against the migration of blood cells intothe extraction fluid outlet channels 310 and 314. Inlet filters 324 and326 may also be provided to guard against introduction of largerparticles into the extraction channel 302 and to smooth the flow ofextraction fluid into the extraction channel 302. The size of the poresshown in filter 330 are greatly exaggerated for the purposes ofillustration only. Preferably, the actual pore size is less than 1000 nmin diameter and more preferably, 600 nm or less. Even more preferably,the size is about 100 nm, but may be still smaller, for example, 10 nm.

The particular fabrication process described above is for purposes ofillustration only. For example, the dimensions of extraction channel 300may be altered without departing from the scope of the presentinvention. FIG. 5 shows an outline of another embodiment of anextraction channel 500. sample fluid enters an extraction channel 502through inlet channel 506 and leaves through outlet channel 512. In thisexample, inlet channels 504 and 508 and outlet channels 510 and 514 donot form 90-degree angles with the length of the extraction channel 502.Thus, for example, the opening 522 and the filter 530 of outlet channel514 faces the direction of flow.

FIG. 6 shows an example of filter 330. Filter 330 contains pores 602selectively sized to exclude components having a particle size largerthan the pore diameter. The diameter of pores 602 can vary according tothe components intended to be excluded from outlet channel 310 and 314.The diameter of pores 602 can range from several micrometers to about 10nm. Thus, although a variety of components of the sample fluid canmigrate into the extraction fluid layers while the fluids are in theextraction channel, the filters prevent certain particles from leavingthe extraction channel via the outlet channels. For example, ifembodiments of the invention are to be used in a dialysis process toremove substances from human blood, a filter pore size of, for example,about 300 nm can be selected to exclude blood cells, thereby preventingthe loss of blood cells from the blood fluid being treated, whilesimultaneously avoiding contact between the blood fluid and the filter.

As mentioned above, filters can be included in openings 316 and 318 ofinlet channels 304 and 308. Including filters in these openings helps tostabilize the introduction of extraction fluid by facilitating an evendistribution of fluid into extraction channel 302. As with filters 328and 300 in outlet channels 310 and 314, a shear flow across the surfaceof the filter is preferably maintained. In addition, the filters preventingress of undesirable components into inlet channels 304 and 308. Thefilters may be particularly useful in embodiments in which there areperiods of time when there is no extraction fluid flow, but a samplefluid is flowing into extraction channel 302 via sample inlet 306.Although the pore size of a filter at the outlet and inlet may beuniform across a given filter, the pore size of an inlet filter may bedifferent from that of an outlet filter.

One example of a commercially available device which can be used for thefilters described above is a microsieve micro filtration device(available from Aquamarijn Micro Filtration BV, Berkelkade 11, NL 7201JE Zutphen). These filters surfaces can be created usingphotolithographic silicon chip manufacturing techniques and othertechniques. For example, a filter can be created by coating a 600 μmthick silicon wafer with a layer of silicon nitride approximately 1 μmthick. A pore pattern can then be created in the silicon nitride layerusing current state-of-the art photolithographic masking and etchingtechniques. After etching the silicon nitride layer, the silicon layercan then be roughly etched to expose the underside of the siliconnitride layer, thereby creating a flow path through the pores. Somesilicon is allowed to remain during the etching process in order toprovide support for the relatively thin silicon nitride layer. Also, thefilter component may include multiple parts, such as the filter 330along with a support component (not shown) to which it can be adhered.

The properties desired in the filters include a smooth and regularsurface to permit the extraction channel flow to scour them clean and tohelp prevent the trapping of cells or macromolecules on the surfacefacing the extraction channel. In addition, the channels defined in thefilter preferably form a regular array which are preferablynon-serpentine, preferably non-branching. Preferably, also, the filtersdefine a smooth and direct flow path for the filtered fluid and a smoothsurface facing the flow inside the extraction channel. The filter,including any support structure, should also be such that particles flowdirectly through the pore channels without adhering or being trapped insmall surface features. The technology for creating such filters and thematerials of which they are made, are numerous and it is expected thatthey will continue to be developed and refined. The invention is notlimited to any particular method for making or structure for thefilters, though the properties described are preferred for embodimentsin which blood or blood fluid is processed.

FIG. 7 shows a close-up side view of the area around opening 322 ofoutlet channel 314 shown in FIG. 3. In the figure, an extraction fluidlayer 702 is shown flowing along the bottom of extraction channel 302,and a sample layer 704 is shown flowing on top of extraction fluid 702.Flow lines 706 indicate the direction of flow. As extraction fluid 702is drawn through filter 330, the extraction fluid layer is drawn downtoward the filter 330 as indicated by the curved boundary 707 of theextraction fluid layer 702. The extraction fluid 702, as it approachesthe filter 330, has a downward flow component 710 and a forward flowcomponent 712, the resultant being shown at 708. Forward flow component712 acts to sweep the surface of filter 330. Thus, any componentscontained in extraction fluid 702 that gather along the surface offilter 330 are swept along the surface of filter 330 in the direction offorward flow component 712. This sweeping action eventually returns theexcluded components to sample layer 704.

Note that the border 707 is not precisely representative of the flowpattern and is intended merely suggest that the extraction layer 702,which sheaths the sample layer 704, is substantially drawn into outletchannel 314. Also note that the boundary between extraction 702 andsample 704 layers is not well-defined. In fact, in an embodiment, theextraction channel 302 is constructed such that all the components aresubstantially blended except for blood cells, which tend to migratetoward the central low fluid shear region of the extraction channel flow702.

FIG. 8 shows a membraneless separator 800 that is similar to the device300 described above. The membraneless separator 800 includes anextraction channel 802, three separate inlet channels 804, 806 and 808and three corresponding outlet channels 810, 812 and 814. Membranelessseparator 800 has filters 816 and 818 placed in inlet channels 804 and808 and has filters 820 and 822 on outlet channels 810 and 814. It willbe understood, however, that the invention is not limited by the numberof inlet or outlet channels used, nor is the invention limited byrequiring each inlet and outlet channel to have a filter. As illustratedin FIG. 8, membraneless separator 800 can be used as a plasmapheresisdevice. For example, as shown in FIG. 8, plasma from the blood enteringextraction channel 802 through inlet channel 806 is skimmed and exitswith extraction fluid through outlet channels 810 and 814. This processof skimming is accomplished by withdrawing a greater volume ofextraction fluid from outlet channels 810 and 814 than is provided byinlet channels 804 and 808. Thus, this excess volume is removed from theblood fluid. FIG. 8 illustrates a simplification of the layeredstructure of the flow through the extraction channel 802. In theembodiment illustrated, the sample fluid entering inlet channel 806 andextraction fluid entering inlet channels 804 and 808, and forming layersindicated at 809, undergo progressive change in composition as theircontact time increases. As a result, a mixing layer 811 may becharacterized where components from both fluids are present in the sameproportion. Since there is a tendency for blood cells to migrate towardthe low-shear flow centerline of the extraction channel 802, the mixinglayer 811 is free of blood cells derived from the sample fluid 806. FIG.8 illustrates the fact that, at least non-cellular components from thesample layer which enter the mixing layer 811, exit the extraction fluidoutlet channel 810. The extraction fluid may include a net gain involume, thereby, since the mixing layer 811 is shared between the samplefluid outlet channel 812 and each of the two extraction fluid outletchannels 810 and 814.

It should be clear that the illustration of FIG. 8 is figurative and inreality the mixing layer 811 is not distinct with clear boundaries, asdepicted. Also, it should be clear from the above discussion andembodiments, that the extraction channel 802 can be used to separatecellular components from blood or to extract cell-free plasma, even inthe absence of extraction fluid. The cell-free blood fractions can beeffectively skimmed from the layers of the extraction channel fluidwhich will be relatively free of cells due to the shear-inducedself-diffusion of the cells to the center of the flow. This same effectcan also be used to concentrate cells in the absence of extractionfluid. The filters (e.g., 822) at the outlets near the walls of theextraction fluid may help to prevent cells from being present in thecell-free fractions taken from the extraction channel 802.

In preferred embodiment of a renal replacement therapy device, theextraction channel operates in conjunction with a secondary processorthat receives extraction fluid from an extraction fluid outlet of theextraction channel, processes the extraction fluid externally of theextraction channel, and returns the extraction fluid to an extractionfluid inlet of the extraction channel. FIG. 9 shows a simplified blockdiagram of a system 900 including extraction channel 902 and secondaryprocessor 904. Although not shown in detail, it will be understood thatextraction channel 902 can have features shown in FIGS. 3 to 8 anddescribed above respect to the various extraction channel embodiments.Blood that is to undergo processing is provided to (and removed from)extraction channel 902 through inlet line 928 and removed through outletline 920. Meanwhile, extraction fluid that is recycled by secondaryprocessor 904 is also provided to (and removed from) extraction channel902 by inlet line 930 and outlet 932, respectively. Thus, in thisexample, there are three fluid streams. The first fluid stream is theblood fluid to be processed carried in inlet and outlet lines 928 and920. The second fluid stream is the extraction fluid (i.e., extractionfluid or secondary fluid), which contacts the blood fluid in extractionchannel 902 and is carried in inlet and outlet lines 930 and 932. Thethird fluid stream is used to exchange components with the extractionfluid to refresh it and is carried into and out of the secondaryprocessor through inlet and outlet lines 906 and 908, respectively. Asalso shown in FIG. 9, secondary processor 904 exchanges solutes with thethird fluid (e.g., dialysate) across a membrane refreshed by acontinuous fresh supply. The third fluid is introduced through inletline 906 and is output through outlet line 908 after being used by thesecondary processor 904. Thus, the extraction channel 902 equilibratessolutes between the sample fluid and the extraction fluid while keepingcells from contacting large area artificial surfaces such as those of amembrane in the secondary processor or the walls of the extractionchannel 902.

The secondary processor 904 can use a variety of mechanisms to changethe received extraction fluid such that a desired interaction with thesample fluid is achieved. In addition to ultrafiltration, diafiltration,and dialysis, these include sorption, using sorbents targeted toparticular small and/or large molecules, chemical reaction, andprecipitation. The following international publications describeexamples of suitable hemodiafilters: WO 02/062454 (Application No.PCT/US02/03741), WO 02/45813 (Application No. PCT/US01/47211), and WO02/36246 (Application No. PCT/US01/45369). Moreover, when low-molecularweight solutes are removed by diafiltration in the secondary processor,a stream of sterile buffer is preferably added to the blood to provide agreater volume of fluid, and accompanying small molecules, to passthrough the diafiltration membrane in the secondary processor. Inconventional diafiltration, such replacement fluid is added before orafter the diafilter. In the described embodiment, however, it isadvantageous to add it either to the bloodstream or the recycle fluidfrom secondary processor 904, which is the primary source of extractionfluid.

It will be noted that the secondary processor, working in conjunctionwith the extraction channel will automatically tend to balance theoutflow of macromolecules from the extraction channel against the inflowof macromolecules which have been retained by the secondary processorand conveyed back to the extraction channel. Thus, the secondaryprocessor regulates the operation of the extraction channel through thecomposition of the recycle stream that it returns to the inlets forextraction fluid of the extraction channel.

In blood therapy, one example of a macromolecule which it is desirableto retain in the blood is serum albumin. In each pass through adiffusion-based exchange device, such as the extraction channelembodiments described, albumin would diffuse at no more than ¼th therate of small solutes. However, in a renal replacement therapytreatment, a given volume of blood must pass multiple times through theexchange device in order to remove urea from the body because isdistributed throughout the total body water compartment. Thus, urea mustbe picked up from the tissue by a urea-depleted volume of blood andpassed to the extraction fluid to be replenished, whereupon the samevolume, perhaps ten times in a treatment, returns to the tissues to pickup more urea and deliver it to the extraction fluid. So while albumindiffuses slowly compared to urea, a given molecule of albumin has manymore opportunities to be picked up by the extraction fluid. As a result,the fractional removal of albumin, even though its inherent diffusionrate is smaller, may tend to exceed the fractional removal of urea.

The secondary processor (e.g., a membrane device that permits extractionof urea and water but not albumin) can be used to ensure against theremoval of albumin to the blood by returning it in the extraction fluidprocessed by the secondary processor. In contrast, urea is removed fromthe extraction fluid by the secondary processor and extraction fluid isreturned to the extraction channel, depleted of urea. The refreshedextraction fluid is therefore able to pick up more in the extractionchannel. As mentioned, the returning stream of extraction fluid may alsohave a selected water content as well. Thus, the composition of thisstream will recruit the further extraction of urea and water but willnot recruit further extraction of albumin, given that the difference inalbumin concentration between the blood being processed and theextraction fluid will have disappeared.

The difference between the inlet flow rate and the outlet flow rate ofthe extraction fluid can be controlled to control the compositions ofthe exiting sample and extraction fluid streams. In the renalreplacement therapy embodiments, if the rate of outflow of theextraction fluid from the extraction channel is equal to its rate ofinflow, even when urea is removed by the secondary processor, a net flowof albumin and other macromolecules into the outgoing extraction flowwill automatically be balanced by a net inflow back into the sample(blood) stream. If there is a higher fluid volume rate of removal fromthe extraction channel from the rate at which fluid is returned to theextraction channel, the patient's water volume will be reduced by thewater draw-down. The concentration in the extraction flow, which is aclosed loop, increases until the concentration of macromolecules,including albumin, rises in the recycle stream to match the level in thesample stream such that a transport balance is maintained and no netloss of such components obtains, except for any which may remain in theextracorporeal circuit after treatment is terminated.

When the principal goal of the treatment is the removal of highlydiffusible (in general, low molecular weight) molecules, assuming a flowof 20 ml/min flow, the contact area in the extraction channel will be inthe range about 17 to 71 cm². When the principal goal of the treatmentis the removal of slowly diffusible molecules (e.g., proteins andespecially immunoglobulins), the contact area in the extraction channelwill be larger, in the range of approximately 1,700 to 7,100 cm²(assuming a flow of 20 ml/min), and the secondary processor can beconfigured to remove these molecules and to recycle smaller molecules(unless their simultaneous removal is desired).

A more detailed view of a membraneless separator embodiment, consistentwith the embodiment of FIG. 9, is shown in FIG. 10. Blood treatmentsystem 1000 includes an extraction channel 1002 and secondary processor1004. The extraction channel 1002 has inlet channels 1008, 1010 and 1012that lead to inlets 1020, 1021, and 1022, respectively. The inlets 1020and 1022 receive extraction fluid from inlet channels 1008 and 1012,respectively. The inlet 1021 receives sample fluid from inlet channel1010. The inlets 1020 and 1022 may or may not be filtered as describedabove. The extraction channel 1002 also has outlets 1024, 1025 and 1026.The outlets 1024 and 1026 receive extraction fluid and convey the sameto outlet channels 1014 and 1018, respectively. Sample fluid leaves theextraction channel 1002 through outlet 1025 which conveys the samplefluid to outlet channel 1016. The outlets 1024 and 1026 may or may notbe filtered as described above. Preferably, filters are provided andhave a pore size of about 100 nm, although the pore sizes could haveother sizes as explained above.

System 1000 also includes a blood supply 1028 and a blood reservoir 103(which, in a treatment setup, would both correspond to a living animalor human patient). A plurality of pumps 1029. 1030, 1032, 1034 arepreferably automatically operated. A blood supply 1028 provides blood toextraction channel 1002 through a blood inlet channel 1010. Blood supply1028 is preferably whole blood from a living animal but can also be anartificial reservoir. Blood withdrawal pump 1030 removes blood from theextraction channel 1002 through blood outlet channel 1016 and conveys itto the blood reservoir 1030, which may be the same as the blood supply1028 as mentioned. Also, preferably a blood pump 1029, though notnecessarily essential, can be provided in line 1010 to pump blood fromthe blood supply 1028 to the extraction channel 1002.

The flow of extraction fluid into extraction channel 1002, throughsheath inlet channels 1008 and 1012 through inlets 1020 and 1022, iscontrolled by extraction fluid injection pump 1032 (which preferablyprovides extraction fluid in equal parts to channels 1008 and 1012). Theflow of extraction fluid out of extraction channel 1002, through outlets1024 and 1026 and into outlet channels 1014 and 1018 is controlled byextraction fluid withdrawal pump 1034, which preferably draws equalamounts of extraction fluid out of channels 1014 and 1018. Pump 1034 maybe a double pump such as a two-chamber pump or two peristaltic pumpswith rotors on a common shaft. Alternatively two separate pumps (notshown) can be use on each of the lines 1014 and 1018 andfeedback-controlled to balance the flow through the lines 1014 and 1018while regulating the total flow of extraction fluid from the extractionchannel 1002. Pump 1032 may also be a double pump such as a two-chamberpump or two peristaltic pumps with rotors on a common shaft (not shown).Pump 1032 may be replaced by two separate pumps (not shown) on each ofthe lines 1008 and 1012 which are feedback-controlled to balance theflow through the lines 1008 and 1012 while regulating the total flow ofextraction into the membraneless processor 1002. The use of separatepumps can also provide the ability to convey different fluids, or thesame or different fluids at different rates, to inlet channels 1008 and1012. Thus, the extraction fluid entering inlet channel 1008 can besubstantially similar to, or different from, the extraction fluidentering inlet channel 1012. It should be understood that the inventionis not limited by the particular types of pumps or flow rates and itshould be clear that many variations are possible.

Pumps 1029, 1030, 1032, and 1034 (or other possible pump arrangements)can be used to control the flows of the extraction fluids and bloodfluid so as to withdraw only the extraction fluids or the extractionfluids plus a prescribed amount of blood fluid through filters 1024 and1026. Likewise, pumps 1030, 1032, and 1034, and if present, pump 1029,can be controlled to regulate the flows of the extraction fluids andblood fluid to regulate the contact between the cell-containing samplelayer and filters 1020 and 1022. In a preferred configuration, thecontrol is such that water volume to be drawn down from a patient isperformed at as low a rate as possible and therefore that the netdraw-down be accomplished over a maximum duration consistent with thedesired treatment time and patient requirements. The water draw-down isaccomplished by drawing a larger volume through the outlet channels 1014and 1018 than replaced through the inlet channels 1008 and 1012. Thus,the pumps are preferably controlled to minimize the difference in outletand inlet flow rates and to regulate the two rates precisely. Inaddition, the outlet flow rates through line 1014 and line 1018 arepreferably kept precisely the same to avoid sucking the cell-containinglayer through one of the extraction fluid outlet lines 1014 and 1018 asa result of an imbalance. By precisely regulating the mean andinstantaneous flow rates, the interface between the centercell-containing layer and the fluid outlets 1025 can be maintained toensure that a minimum of blood cells contact the extraction channel 1002walls or the filters 1024 and 1026, which is preferred.

System 1000 can also include an extraction fluid reservoir 1036.Extraction fluid reservoir 1036 provides a supply of fresh extractionfluid (e.g. such as replacement fluid used in hemofiltration ordialysate for preferred blood treatment embodiments) to the flow loopbetween extraction channel 1002 and secondary processor 1004. Undernormal operation of some embodiments, components of the blood fluid thathave diffused into the extraction fluid are removed by secondaryprocessor 1004. Under certain conditions, blood cells or other bloodfluid components, such as fibrinogen, that diffuse into the extractionfluid from the blood fluid may collect along the surface of outletfilters 1024 and 1026. These materials can be removed from the surfacesof filters 1024 and 1026 by temporarily reversing the flow of theextraction fluid to flush the filters 1024 and 1026 using only a smallquantity of extraction fluid. This amount of extraction fluid can bereplenished from extraction fluid reservoir 1036 upon reestablishingnormal co-current flow of extraction fluid relative to the blood fluid.The need to perform this “blowback” operation can be determined bypressure drop across the filters or flow measuring devices. Thesedevices can be integrated into system 1000. The extraction fluidreservoir can also serve as a source of replacement fluid fortreatments, where more water and solute volume are deliberatelyeliminated in the secondary processor than are to be eliminated from thepatient for treatment purposes, as is done in hemofiltration, forexample. The pumps may be automatically controlled by a controller 1040,which preferably includes a programmable processor.

Preferably, in blood treatment embodiments, the extraction fluidprovided to extraction channel 1002 (from separator 1004 and/or optionalextraction fluid reservoir 1036) by extraction fluid injection pump 1032occupies approximately ⅔ of the cross-section of extraction channel1002, with blood from blood supply 1028 in the middle ⅓. (This flowconfiguration is illustrated in FIG. 1A.) This configuration can bemaintained by appropriately regulating the inflow of blood andextraction fluid. In this configuration, each half of the blood layer inextraction channel 1002 is “serviced” by one of the sheathing layers,and the sheathing layers are traveling at an average velocity that isapproximately half that of the blood, though the interfacial velocitiesof the blood and extraction fluids are approximately equal. Thus, thevolume of blood and the volume of extraction fluid that pass through theunit in a given period of time are approximately equal. Although theinvention is not limited in this manner, it should be noted that, in theconfigurations described here, the exchange efficiency drops, from themaximum of 50% associated with equilibrium, when the volumetric flows ofthe two fluids (e.g., blood and extraction fluid) are different fromeach other.

In order to cause the separation (or skimming) of all or part of thecell-free component of the blood being processed, the inlet and exitflows of the extraction fluid may be controlled (via pumps 1032 and1034, respectively) such that more total fluid is withdrawn fromextraction channel 1002 through outlet channels 1014 and 1018 thanextraction fluid provided through inlet channels 1008 and 1012. Thus, aportion of the blood being processed is removed along with theextraction fluid through outlet channels 1014 and 1018. For example, itis possible to skim 10% of the blood flow by running extraction fluidwithdrawal pump 1034 at a rate that is 10% higher than the rate ofextraction fluid injection pump 1032. It will be appreciated that, whenthis is done, the blood efflux rate is determined and need not becontrolled, as it should naturally have an outflow that is 90% of theinflow.

As explained above, when indiscriminate plasma removal is not desired,the plasma that is skimmed from the blood using extraction channel 1002is processed by secondary processor 1004, which regulates the operationof the extraction channel 1002 through the flow rate and composition ofthe recycle stream that it returns to sheath inlet channels 1008 and1012 (i.e., a recycle stream is used to limit transport of bloodcomponents for which extraction is not desirable). A substantial benefitarises because secondary processor 1004 is able to achieve highfiltration velocities due to the fact that concentration polarization islimited to proteins and does not involve cells. Moreover, because cellsare retained in extraction channel 1002, though the action of cellmigration (described below), supplemented by the action of the filters,a majority of these cells would see artificial material only on itsconduit surfaces. While some relatively small amount of cells maycontact the filters 1024 and 1026 in outlet channels 1014 and 1018, thecontact is limited to a small fraction of the total number of cells andoccurs for a relatively short time. Because cell contact on theliquid-liquid contact area is far less traumatic, mechanically andchemically, a reduction in bio-incompatibilities and a reduced (oreliminated) need for anticoagulation is achieved. Additionally, becausethe primary transport surface in the system is intrinsically non-foulingand the surface of the filters is swept clean by the fluid shear rate, amajor deterrent to long-term or continuous operation is removed, openingthe possibility of a wearable system with the recognized benefits ofprolonged, slow exchange.

It should be understood that operation of extraction channel 1002 thatallows the sheath exit flows to be larger than the corresponding inletvalues will induce a convective flow from the blood stream, over andabove the diffusive flow. In order to prevent such a convective flowfrom carrying blood cells with it (as would be the case if thedistribution of cells in the blood stream was uniform), it is importantthat cellular components of the blood have migrated to the center of theblood stream in order to permit significant plasma skimming. Centripetaldrift of cells occurs under a variety of flow regimes in the disclosedembodiments. The flow conditions can be adjusted to cause blood cells tomove away from the blood-liquid interface. For example, when blood flowsin a tube below a wall shear rate (measured as the blood-flow velocitygradient perpendicular to the tube wall) of about 100 reciprocalseconds, this shear rate causes cellular components to migrate to thecenter of the tube. Thus, the occurrence of cell contact with thefilters is reduced. (See Goldsmith, H. L. and Spain, S., Margination ofleukocytes in blood flow through small tubes, Microvasc. Res. 1984March; 27(2):204-22.).

It will be appreciated that long-term stability is necessary forsatisfactory operation of the microfluidic devices described herein. Forexample, it is desirable to prevent inappropriate differences in sheathinlet and outlet channel flows, which, uncorrected, could result inunintended infusion of sheathing solution into the bloodstream.Accordingly, on-board electronics and photonics (not shown), which arecommon features of chip-based microfluidic devices, can be used toregulate system 1000 (e.g., to introduce flow changes) with anelectrically activated device (e.g., a piezoelectric valve) that ismounted on the same plate, or “chip,” on which extraction channel 1002is located.

An ultramicroscope (or other device that is sensitive to the presence ofdilute particles) can be used to monitor the fluid exit stream in theextraction fluid outlet channels 1014 and 1018 for the presence of cellsin the extraction fluid, as might occur on failure of one of filters1024 and/or 1026 on the outlet channels. Additionally, controls arepreferably provided to protect against flow imbalances that might causeblood losses or hypervolemia, which are naturally prevented when amembrane is present but which may occur in a membraneless device. Forexample, a control system may be provided which shuts down the systemand initiates an alarm when cells are detected in the extraction fluidoutside the membraneless processor or when independent flow measuringsensors detect a flow imbalance between blood and net sheath flow beyonda threshold imbalance, which might obtain when a prescribed quantity ofplasma is removed or when hypervolemia is being treated.

As explained above, in the extraction channel, the fluids (e.g., bloodand extraction fluid) preferably flow in the same direction. Inparticular, flow in opposite directions tends to disrupt the blood-fluidinterface and induce undesirable mixing. When fluids flow in the samedirection, the greatest exchange rate that can be achieved obtains whenequal volumes of fluids the sheath and blood streams achieve equilibrium(which, according to Loschmidt's formula provided above, means that ifthe extraction fluid flows at the same rate as blood, the extraction Eof a solute cannot exceed ½). In other words, if the two flows areequal, at most half of the solute can be transferred. Moreover, whilegreater flows permit larger fractions, E, of a solute to be removed,they require higher circulation rates to the secondary processor andthus force processing of solutes at lower concentrations, which isgenerally undesirable. Therefore, it is generally desirable for theseflows to be nearly equal, or at least within a factor 3. Of course, thisdescription applies where the sample and extraction fluids have similarproperties, such as their capacity to store solutes and/or otherexchanged components, and the proportions can be adjusted accordinglywhen fluids with differing properties are used.

This limitation on extraction efficiency can be overcome by aconfiguration shown in FIG. 11 and described below which achieves theeffect of opposing flows (counterflow) by the interconnection of morethan one concurrent membraneless processor. In particular, lowextraction efficiency can be overcome by more sophisticated layouts of amicrofluidic system such that flows are concurrent in each unit of thesystem, but the overall flow approaches countercurrency in pattern andefficiency.

Subdivision of a given desired contact area into n units (stages) eachconnected to the other in a countercurrent manner is used to allowextraction efficiency to rise above 50%. Although FIG. 11 shows anexample of a two-stage membraneless separation system, other embodimentscan have more than two stages. Each addition stage results in anincrease in extraction. Referring to FIG. 11, a two-stage membranelessseparation system 1100 has a first stage extraction channel 1102 and asecond stage extraction channel 1104. The system 1100 also includes asecondary processor 1106, also described above, for removing componentsfrom the extraction fluid between the two stages 1102 and 1104. A samplefluid is fed into a sample inlet 1108 of the first stage extractionchannel 1102 at a sample fluid flow rate of q_(S), having aconcentration of a given component of c₀. The sample fluid exits firststage extraction channel 1102 through a sample outlet 1110 and enters asample inlet 1112 of second stage extraction channel 1104 at aconcentration of c₁. The flow of sample fluid is assumed to beapproximately equal throughout both stages. Finally, the sample fluidexits second stage extraction channel 1104 by a sample outlet 1114 at aconcentration of c₂.

A clean extraction fluid is fed into an extractor inlet 1116 of secondstage extraction channel 1104 at an extraction fluid flow rate q_(E) theflow of extraction fluid is assumed to be approximately equal throughoutboth stages. Because the extraction fluid is clean, the concentration ofthe given component will be assigned a value of zero. The extractionfluid exits second stage extraction channel 1104 through an extractoroutlet 1118 and enters first stage extraction channel 1102 through anextractor inlet 1120. If sufficient contact area between the samplefluid and extraction fluids is maintained in each extraction channelstage 1102 and 1104 for a sufficient time, as determined by thecalculations above, the concentration of the given component willapproach equilibrium between the sample fluid and the extraction fluids.Thus, the concentration of the extraction fluid leaving extractor outlet1118 of second stage extraction channel 1104 is assumed to be equal toc₂. The extraction fluid exits first stage extraction channel 1102 by anextractor outlet 1122 and is returned to secondary processor 1106through an extractor inlet 1124. As with second stage extraction channel1104, the concentration of extraction fluid exiting outlet 1122 isassumed nearly equal to the concentration of the exiting sample fluid.Thus, the concentration of the extraction fluid is c₁. The componentscollected by the extraction fluid are removed in secondary processor1106 so that clean extraction fluid exits secondary processor 1106 by anextractor outlet 1126 and can be recirculated to extractor inlet 1116 ofsecond stage extraction channel 1104. Mass balance calculations may beperformed for each stage of the two-stage membraneless separation system1100 in order to find the fractional clearance Cl/q_(S) of the givencomponent. Using the concentration and fluid flow variables definedabove, the first stage extraction channel 1102 mass balance can bewritten as q_(S)c₀+q_(E)c₂=(q_(S)+q_(E))·c₁. The second stage extractionchannel 1104 mass balance can be written asq_(S)c₁+q_(E)0=(q_(S)+q_(E))·c₂ where c₀=1, and the fractional clearanceCl/q_(S) is equal to 1−c₂, and the relationship between the fractionalclearance and extraction/sample fluid flow ratio is

$\frac{Cl}{q_{S}} = {\frac{\lambda^{2} + \lambda}{\lambda^{2} + \lambda + 1}.}$

Thus, Cl approaches the value of the sample fluid flow as approachesinfinity. When the extraction fluid flow total is twice that of thesample fluid flow (i.e. λ=2), the fractional clearance is approximately0.86. In contrast, in a non-staged, single pass membraneless separationsystem, the best efficiency is equilibration of each half of the samplefluid with the corresponding extraction fluid in contact with that halfof the sample fluid. Therefore, the two-stage extraction channel system1100 is more efficient than the single-pass system at removingcomponents from the sample fluid at equal extraction fluid flow rates.While two stages are shown in FIG. 11, any number of stages (e.g., 3, 4,5, or more) can be used in system 1100, all of which can be easilyprovided on a single substrate or set of substrates, fabricatedaccording to known techniques for the fabrication of microfluidicdevices. Thus, in a preferred embodiment, the multiple stages can beprovided without introducing any external connections betweenmicrofluidic stages.

In a preferred embodiment, each of the extraction channels has filters,of the type described with regard to FIGS. 3-8, in the extraction fluidoutlets 1122 and 1118. In one embodiment, only the extraction fluidoutlet 1122 that is connected to the secondary processor 1106 isfiltered.

The devices, systems and methods disclosed, with the appropriateselection of filter pore size, are capable of diffusing various bloodcomponents having different sizes, including ‘small molecules, ‘middle’molecules, macromolecules, macromolecular aggregates, and cells, from ablood sample to the extraction fluid. This ability is particularlyimportant considering the fact that different treatments require theremoval of different sized particles. For example, in dialysis, one maydesire to remove molecules of low molecular weight, while in thetreatment of acute liver failure, both small and intermediate-sizedmolecules are to be removed. In therapeutic apheresis, meanwhile, onegenerally wishes to remove selected protein macromolecules (e.g.,immunoglobulins), while in the treatments for fulminating sepsis, it istoxins of intermediate molecular weight that one generally desires toremove. On the other hand, in proposed anti-viral treatments, one wishesto remove free viral particles, while in the treatment of congestiveheart failure, one simply wishes to remove water and a non-selectivecohort of electrolytes.

The treatment to which extraction fluid is subjected in the secondaryprocessor may be substantially the same as those performed in thevarious types of conventional treatment using whole blood or cell-freeplasma. A secondary processor can include any of a variety of devicesused for refreshing the extraction fluid. For example, a membrane deviceor a sorption device could be used. In addition, the extraction channeland secondary processor system is not limited to application to renalreplacement therapy. For example, such a system can also used to remove,destroy or inactivate a substance related to a specific disease.Examples include enzyme reactors, cryoprecipitators, and/or ultravioletirradiators. The system can also be used for extracting components froma non-blood sample fluid, in which a secondary processor receives theextraction fluid and at least some of the components of the sample fluidwhich are not to be removed.

Note that although in the foregoing and following discussions, althougha single extraction channel and a single secondary processor may beidentified, it is assumed that the singular nouns do not necessarilyrefer to a single component. For example, multiple extraction channelsmay be formed in a layered or folded structure to achieve compactnesswith high contact area between sample and extraction fluids.

The interface between the first extraction fluid and the sample fluid,within the extraction channel, can be varied by adjusting the relativeflow rates of the first extraction fluid and the sample fluid.Additionally, a detector may be placed in the outlet receiving stream orstreams to detect substances in the exiting fluid(s), for example,undesirable blood components in the exiting extraction fluid or withinthe extraction channel. A signal from the detector may then be used toadjust the relative flow rates of sample and extraction fluids. Anexample of a detector is an opacity monitor or ultramicroscope in theextraction channel which can detect erythrocytes in the extractionchannel outlet which should receive non-cellular fluid. Another exampleof a detector is a hemoglobin detector which may indicate the rupture ofblood cells due to improper fluid flows. Total and relative extractionand sample fluid flow rates can also be adjusted to correct such acondition.

A method is described for selectively extracting components from asample fluid includes providing a microfluidic extraction channel havingat least a first inside surface and a second inside surface andestablishing laminar flows of a first extraction fluid, secondextraction fluid, and sample fluid within the microfluidic extractionchannel. The laminar flow of the first extraction fluid within theextraction channel is in contact with the first inside surface of theextraction channel, and the laminar flow of the second extraction fluidwithin the extraction channel is in contact with the second insidesurface of the extraction channel. The laminar flow of the sample fluidis disposed between and in contact with the first and second extractionfluids within the extraction channel. The first extraction fluid and afirst portion of the components of the sample fluid are withdrawn fromthe extraction channel through a first filter, the first filter havingpores sized to exclude components larger than a first size. Likewise,the second extraction fluid and a second portion of the components ofthe sample fluid are withdrawn from the extraction channel through asecond filter, the second filter having pores sized to excludecomponents larger than a second size. The remaining sample fluid iswithdrawn from the extraction channel.

As mentioned above, the embodiments described herein allow thepurification of blood without the use of a membrane by contact of theblood with a miscible fluid under conditions that prevent turbulentmixing. It is appreciated that embodiments described herein are usefulin hemodialysis, for example. However, it should also be noted that theembodiments, and variations thereof, are also useful in other situationswhere exchange between a sample fluid and another fluid is desired via adiffusion mechanism.

The interface area provided by the extraction channel for a specifiedexchange rate can be achieved by appropriate combinations of channellength, width, and number according to the principles described herein.The required area can be obtained by providing multiple extractionchannels and by providing a sheathing flow so that each channel containstwo interfaces. It is shown herein that the competing requirements ofsmall height (to avoid excessive diffusion times and in-processvolumes), short length (to avoid excessive pressure drop) and practicallimitations on width of a single device, which suggests the need toarray them in parallel, side-by-side or in a stack can be satisfied inpractical microfluidic devices.

The described embodiments can be used to process the blood of a singleindividual for the purpose of treating a large number of diseaseconditions. For example, therapies described above can be used in thetreatment of acute renal failure, acute liver failure, high antibodylevels in myasthenia gravis and other autoimmune diseases. Additionaluses include, for example, the removal by either precipitation orsorption of LDL in homozygous hyperlipidemia, in addition to the removalof malignant sepsis or fluid in cases of congestive heart failure, forexample. The described embodiments can also be used to aid in thereduction of viral burdens in AIDS patients, as well as for treatment ofpatients requiring other types of blood purification. Patients withdiabetes, patients that have suffered a drug overdose, patients thathave ingested a poison, patients suffering from renal failure, patientssuffering from acute or chronic liver failure, or patients that haveMyasthenia gravis, lupus erythematosis, or another autoimmune diseasecan also benefit from the devices and systems described above. Forexample, while an exchange device according to the invention is not acure for diabetes, it can be useful in the amelioration one or moresymptoms of diabetes. Moreover, the embodiment described above could beuseful in clearing the blood of IgG molecules or other molecules, whichare causative of an autoimmunity disorder. Additionally, embodimentsaccording to the invention can be used in acute dialysis or for extendeddialysis. Patients (or animals, in the case of veterinary use) sufferingfrom disorders, diseases and syndromes not listed herein can also betreated.

The membraneless devices and systems described are preferably embodiedin systems that provide extended treatment times, low extracorporealblood volume, it is therefore possible to provide them in a compactconfiguration. In one embodiment, a wearable (or at least portable)system according to the invention can run between 20 and 24 hours perday at a flow rate of about 20 cc/min, for example. The patient couldthen have, for example, 4-5 hours each day without the device in placewhich could be used for personal hygiene (e.g., showers or baths),sports activities, or other activities not amenable to the small systembeing worn or used. The embodiment described above thus addresses aproblem recognized by the dialysis community (e.g., the negative sideeffects such as physical exhaustion, thirst, etc. associated with anepisodic dialysis schedule), for which daily or nocturnal hemodialysisis not always a sufficient alternative. In particular, the embodimentdescribed herein allows the patient to move about in a normal manner(e.g., go to work, school, home, etc.) while being subject to ongoingdialysis.

In addition to the treatment of various disease states, a device orsystem according to the invention can also be used for extracting bloodcomponents that are useful in treating others, as well as for purposesof studying the processes by which molecules and cells segregate anddiffuse in blood. For example, diffusion of individual molecular speciesin blood may not occur independently and may not depend on size in thesimple manner dictated by the Stokes-Einstein equation. Moreover, manysolutes may partition into multiple forms: free, in complexes, bound toplasma protein, bound to cell-surface moieties, or as intracellularsolutes. Relative to the rate of diffusion of the solute, its differentforms may or may not be in local equilibrium. These phenomena are likelyobscured when a membrane is present because it slows and controlsoverall transfer rates. Therefore, a membraneless device or systemaccording to the invention can be a useful scientific tool to studythese phenomena and a system in which rates are raised enough thatpartitioning may set limits on how much and how quickly a solute can beremoved. A particular example is bilirubin bound to albumin. Anotherexample is inorganic phosphorous which exists as partially ionizedsalts, as two anionic forms in plasma and in several intracellularforms.

Although the present specification is primarily concerned with bloodtreatment for end stage renal disease, extraction of blood componentscan be used to remove other components for treatment, such as free viralparticles and, in the treatment of congestive heart failure, to removewater and a non-selective cohort of electrolytes. Additional uses forextracorporeal processing include extracting blood components useful ineither treating others or in research. Apheresis of plasma (i.e.,plasmapheresis) and thrombocytes, or platelets, is the procedure mostcommonly employed for this purpose. Although the present specificationdiscusses primarily blood processing and issues related thereto, many ofthe methods discussed may be used for processing other fluids as well,such as blood components.

Also, the extraction channel and associated elements discussed hereinmay be used in a secondary processor and may be chained to form multiplestages to select fluid components. For example, a chain of twoextraction channels would convey the extraction fluid of a firstextraction channel to the sample fluid path of a second extractionchannel, thus forming a cascade. The second extractor may have, forexample, filters in its walls with pore sizes that are smaller thanthose of the first such that the sample fluid from the second extractionchannel contains intermediate sized particles, but a reduced fraction ofthe smallest particles. Such a cascade may include an arbitrary numberof stages.

Persons skilled in the art will also appreciate that the presentinvention can be practiced by other than the described embodiments,which are presented for purposes of illustration and not of limitation,and that the present invention is limited only by the claims thatfollow.

While the present invention has been disclosed with reference to certainembodiments, numerous modifications, alterations, and changes to thedescribed embodiments are possible without departing from the sphere andscope of the present invention, as defined in the appended claims.Accordingly, it is intended that the present invention not be limited tothe described embodiments, but that it has the full scope defined by thelanguage of the following claims, and equivalents thereof.

1. A method of performing ultrafiltration, comprising: pumping bloodfrom a human patient into a microfluidic channel to generate a shearflow across the face of filters forming opposite facing walls of themicrofluidic channel, the shear flow in the microfluidic channel beingmaintained at a sufficient magnitude to prevent the clogging of thefilters; drawing plasma through the filters and removing water anduremic toxins from the plasma by passing the same through an ultrafilterat a higher shear rate than would be tolerated by blood due to theconcomitant rate of hemolysis; and returning dehydrated plasma to thepatient.
 2. The method of claim 1, wherein the ultrafilter is amicrofiber bundle type dialyzer.
 3. The method of claim 1, wherein themicrofluidic channel has a depth across the direction of bloodtherethrough of 300 microns or less.
 4. The method of claim 1, whereinthe microfluidic channel has a depth across the direction of bloodtherethrough of about 100 microns.
 5. The method of claim 1, wherein thewidth of the microfluidic channel across the direction of flow is atleast ten times the depth.
 6. The method of claim 1, wherein each of thefilters forming opposite facing walls has an array of holes that areless than 800 nm.
 7. The method of claim 1, wherein each of the filtersforming opposite facing walls has a regular array of holes that are lessthan 800 nm.
 8. The method of claim 1, further comprising pumping theplasma, the pumping controlling a rate of the drawing.